Dolutegravir and R263K

This was originally published here, in French. We provide this translation for your convenience, practical aspects may differ where you live.

Our Summer 2017 series: DOMONO will have been, in fact, a real SUCCESS! - Dolutegravir and the R263K - the R263K: new scenario (DOMONO) - the N155H: new scenario (DOMONO) - Nevirapine and Mono-DTG Switch: the Hunchback Trap - calculation error in the primary hypothesis - DOMONO and the benefit for the patients (not for BigPharma ...)

Absolutegravir, Dolutegravir and the R263K

By Charles Edouard!

Some news from Backy:
A small pick up in ASAT is not a cause for concern; At 5 or 10 times the limit, yes, this would be worrying; You are far from that! This is a successful case of Tivicay® monotherapy; Once settled, you can watch what others do, such as jesuisdu13 who uses mono-Tivicay ® at 4/7 ...

When Dolutegravir mimics Absolutegravir ...

Here, I simplify greatly ... also reread our post on : Absolutegravir, a fantasized molecule.

Absolutegravir is computer-designed on a digitized 'Wild-type' Integrase; a docking software tests millions of configurations. Then, they rerun on mutated, digitized integrases; Finally, on common enzymes to avoid side effects.

In the computer-aided design of DTG, we do not yet have the digitized mutated integrases (besides, which mutations?). So DTG is designed on 'wild-type' integrase and confronted with known mutations of RAL and EVG. Its efficacy, which is assumed to be absolute, is specific to the unmutated 'wild-type' integrase. It is a good start, and more effective than the usual cuisine that gave birth to Raltegravir. Everything is a matter of timing ... I simplify to the extreme, in fact, it's a huge job!

The R263K: a deep Darwinian well

In the very first trials, we observe (by luck or design insight), a phenomenon quite unique in its extent, not seen in test tubes. The mutation of choice of DTG is R263K. It is hard to find in tests tube (known as 'passages'), but it is found in the VIKING trial and in tissue passage tests (a McGill, Montreal, exclusive)

This mutation has two characteristics: it confers a very modest resistance, almost nothing, and the mutated virus has only one desire: stay home: it has no ease to replicate: its low fitness makes it unfit. It's almost a 'Junk'. It falls in its hole and stays there, happily: Let's call this a Darwinian black hole or Darwinian well.

When the pharmacological pressure acts on a wild-type virus, it decreases (without mutating) or mutates with the R263K, which, remarkably, makes the pharmacological pressure even more effective. Conversely, when the pharmacological pressure decreases, the virus regains vigor, including, in the first instance, its R263K mutant. Further, by the effect of "survival of the fittest', the historical virus, wild-type, takes over and we lose track of the mutant.

On a wild-type virus, DTG acts as an Absolutegravir

As long as one remains within this binary system, R263K mutation is beneficial. It is a marker, an epiphenomenon, and it is not the cause of a VL increase (whereas the drop in pharmaceutical pressure is); It accompanies it, kicking and screaming, to finally disappear.

As long as you have a wild-type virus, especially on integrase, Dolutegravir acts as an Absolutegravir. The owners of Absolutegravir will want to keep their trump card until the end, and ViiV HealthCare is not going to come and explain that the naïve patient, with a wild-type virus, has a molecule that has all the advantages of an Absolutegravir.

This is how Lanzafame succeeds with his DTG monotherapies on naïve, selected patients, how I managed Hypodolu (overdosed), Minidolu (Tivicay® 1/4 of a pill, daily) and DTG + 3TC in 1/7

Here is a first clue for reading DOMONO, our summer serial!

Good holiday, good fuck, beware of the sun, and long live the Eclipse!

Comments

Anonymous July 17 2017


Charles-Edouard! July 17 2017


Anonymous July 17 2017


Charles-Edouard! July 17 2017




This was originally published here, in French. We provide this translation for your convenience, practical aspects may differ where you live.

Our Summer 2017 series: DOMONO will have been, in fact, a real SUCCESS! - Dolutegravir and the R263K - the R263K: new scenario (DOMONO) - the N155H: new scenario (DOMONO) - Nevirapine and Mono-DTG Switch: the Hunchback Trap - calculation error in the primary hypothesis - DOMONO and the benefit for the patients (not for BigPharma ...)